The goal of the proposed research is to determine the therapeutic utility of glutaminase inhibitors for the treatment of neurological disorders associated with glutamate excitotoxicity. We will undertake this research using potent and selective small molecule-based inhibitors of glutaminase. Our newly developed 96 well plate-based glutaminase assay is capable of screening a series of compounds synthesized using our new lead glutaminase inhibitor as a template. SAR strategy, interpretation of the data, and optimization of molecular structure will be carefully implemented in consultation with Dr. Norman Curthoys, a world-renowned authority on glutaminase. Potent glutaminase inhibitors with satisfactory pharmacokinetic profiles will be evaluated for their neuroprotective efficacy in animal models of cerebral ischemia. In an attempt to establish the mechanism of action, the most efficacious compound will be used to examine the effect of glutaminase inhibition on the brain level of glutamine and glutamate under the guidance of Dr. Ronald Zielke, a leading expert in using microdialysis for studying brain metabolism. With its research and clinical expertise in glutamate excitotoxicity, Guilford is well positioned to capitalize on this innovative drug discovery opportunity in glutaminase inhibition under this Phase I feasibility study. Positive results in this proposed research will justify Phase II studies ultimately leading to the development and commercialization of a glutaminase inhibitor for the treatment of neurological disorders associated with glutamate excitotoxicity.